Nrf2 (nuclear factor erythroid 2-related factor 2) is a protein in the cap'n'collar transcription factor family that induces cytoprotective genes and plays an important role in protecting against oxidative stress. Under non-stress conditions, Nrf2 is negatively regulated by ubiquitination and proteasomal degradation triggered by Keap1 (Kelch-like ECH-associated protein 1). When Keap1 is exposed to oxidative stimulation and electrophilic stimulation, Nrf2 avoids proteasomal degradation. The Nrf2 then moves to the nucleus, where it forms heterodimers with small Maf proteins and binds to antioxidant response elements (AREs) in antioxidative genes and detoxification genes and induces expression of these genes. This stress response gene regulatory system is called the “Keap1-Nrf2 system”.
In addition to its antioxidative function and detoxification function, the Keap1-Nrf2 system also appears to be involved in metabolic homeostasis, and compounds that activate this system have been considered as potential treatment agents for various diseases (NPL 1, NPL 2). Specific diseases associated with Nrf2 include autoimmune diseases (multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, ulcerative colitis, etc.), central nervous system diseases (Friedreich ataxia, mitochondrial myopathy, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.), malignant tumors (melanoma, lung cancer, medulloblastoma, neuroblastoma, etc.), respiratory diseases (chronic occlusive pulmonary disease, etc.), eye diseases (ocular inflammation, ocular pain, age-related macular degeneration, corneal endothelial disorder, etc.), skin diseases (dermatitis, radiation skin disorders, epidermolysis bullosa, etc.), kidney diseases (diabetic nephropathy, etc.), circulatory diseases (pulmonary arterial hypertension, etc.), liver diseases (hepatitis, liver cirrhosis, etc.), traumatic brain injury, aging, diabetes, obesity and the like.
Compounds having Nrf2 activation ability include sulforaphane, lithospermic acid B (LAB), oltipraz, bardoxolone methyl (CDDO-Me), curcumin and dimethyl fumarate (BG-12), and along with their Nrf2 activating effects, application of these to various diseases has been suggested (NPL 2 and NPL 3).
A compound having a purine ring and a tetrahydrothiophene structure is disclosed in WO 2011/156889 (PTL 1) as a compound having Nrf2 activation ability. However, its basic framework is different from that of a compound having an isothiazole ring structure, and the compound of the present invention is neither disclosed nor suggested.
In the field of drug development, strict criteria must be met not only in terms of the intended pharmacological activity, but also in the areas of absorption, distribution, metabolism, excretion and the like. For example, various tests are required for drug interactions, desensitization and resistance, gastrointestinal absorption upon oral administration, transfer rate into the small intestine, absorption rate and first pass effect, organ barriers, protein binding, induction and inhibition of drug metabolizing enzymes, excretory route and clearance, application methods (application site, methods, object) and the like, and it is rare that all of these criteria are satisfied. However, these problems are common to all medicines.